Acute pancreatitis (AP) can range from a mild self-limited condition to a very severe life-threatening disease. Obesity is a risk factor for development of severe AP. No effective therapies for AP exist, partly as a result of lack of pathologically relevant models for this disease. We developed a novel, pathologically relevant model of AP induced in mice by co-administration of IL-12 and IL-18, two cytokines that participate in the inflammatory response in AP. In this model, obesity highly increases AP severity. The overall aim of this proposal is to identify mechanisms leading to resolution of AP in lean mice and - in contrast - to enhanced disease severity in obese animals, with the ultimate goal of translating these results to the clinical setting. The model of IL-1218- induced AP will be used and results confirmed using the cerulein and sodium taurocholate models. A mild increase in IL-6 and IL-22 levels is observed in lean mice injected with IL-1218, whereas obese mice exhibit a heightened response. In Aim 1, knock-out mice, neutralization experiments and administration of exogenous cytokines will be employed to test the hypotheses that: a) moderate levels of IL-6 and IL-22 mediate the anti-inflammatory and tissue repair responses that lead to efficient resolution of AP in lean animals; b) excessive production of IL-6 and IL-22 in obese mice leads to development of an exacerbated hepatic acute-phase response, with loss of anti- inflammatory and tissue-repair effects in the pancreas. The family of Regenerating (Reg) proteins is highly induced in the damaged pancreas and contributes to tissue repair. Induction of Reg proteins is significantly blunted in the pancreas of obese mice receiving IL-1218. In aim 2, we will test the hypothesis that pancreatic tissue in obese mice is unresponsive to factors that upregulate Reg proteins. Insulin resistance and fatty liver are common traits in obesity. In aim 3, we will test the hypothesis that obesity-associated metabolic dysfunction contributes to increased AP severity in obese mice. The effect of metformin or thiazolidinediones- two drugs commonly used in insulin-resistant patients - on AP severity as well as production of cytokines and acute-phase proteins in lean and obese will be evaluated, together with degree of hepatic steatosis and markers of lipid and glucose metabolism. PUBLIC HEALTH RELEVANCE: This proposal aims at increasing our understanding of the mechanisms linking obesity to increased severity of acute pancratitis, an inflammatory disease of the pancreas for which we do not know the cause and we do not currently have any effective treatments. Although the proposed studies are not aimed at directly generating new therapies for this inflammatory disease, a better understanding of the complex mechanisms involved will be useful for future novel treatments and - ideally - also to design possible strategies to prevent disease.